Project Summary/Abstract: In recent years, a significant increase in mortality of patients with microbial fungal infections has been observed. This is primarily due to a higher incidence of individuals who are immunocompromised including HIV-infected patients, patients undergoing cancer therapy, organ transplant recipients, and patients with advanced stages of diabetes. A complication in treating patients with fungal infections is the development of multidrug-resistant fungi. With the limited number of effective antifungal drugs, the increase of drug resistant fungi, and development of new pathogenic fungi, fungal infections are a major threat to human health. The proposed studies help to solve this issue by identifying underlying causes for drug resistance and to identify additional molecular targets for development of new antifungal drugs that will effectively treat fungal infections or work in combination with current treatments. Our central hypothesis is that SET domain epigenetic factors regulate genes or pathways that alter antifungal drug resistance. This hypothesis was established based on our preliminary observations showing that loss of SET domain coding genes such as SET1, SET3, and SET4 can alter the efficacy of antifungal drugs. This proposal will use S. cerevisiae, the opportunistic pathogen, C. glabrata, and G. mellonella larvae as model systems to identify key epigenetic regulators and to study the impact of epigenetics and epigenetic factors on antifungal drug resistance and pathogenicity. The epigenetic mechanisms that regulate the expression of genes and pathways important for antifungal drug resistance will be identified, a new precursor sterol pathway will be characterized, and the biological and biochemical function of the newly defined epigenetic factor, Set4 will be determined. Overall, studying SET domain proteins and other epigenetic factors will have a positive impact on public health by providing fundamental new insights in the areas of fungal infections and antifungal drug resistance.